Effects of the Neutral Endopeptidase Inhibitor, SCH 42495, on the Cardiovascular Remodelling Secondary to Chronic Hypoxia in Rats

1994 ◽  
Vol 87 (1) ◽  
pp. 109-114 ◽  
Author(s):  
J. S. Thompson ◽  
W. Sheedy ◽  
A. H. Morice
Keyword(s):  
Atrial Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Chronic Hypoxia ◽  
Neutral Endopeptidase ◽  
Pulmonary Vasculature ◽  
Vascular Remodelling ◽  
Plasma Atrial Natriuretic Peptide ◽  
And Control ◽  
Pulmonary Vascular Remodelling ◽  
Atrial Natriuretic

1. We have investigated the effects of inhibition of neutral endopeptidase on the cardiovascular remodelling secondary to chronic hypoxia in rats using a novel neutral endopeptidase inhibitor, SCH 42495. 2. Rats were divided into four groups, two of which were maintained in a normobaric, hypoxic chamber (10% O2) and two in room air. Animals received either neutral endopeptidase inhibitor, SCH 42495 (30 mg/kg), or aqueous methyl cellulose vehicle (0.4%) twice daily by oral gavage. 3. At 1, 3, 7, 10 and 14 days, animals (n = 4 per group for days 1, 3, 7 and 14, and n =8 for day 10) were killed. Hearts were dissected and weighed for determination of ventricular ratios, lungs were perfused with formol saline for histological examination of the pulmonary vasculature, and blood was collected for measurement of plasma atrial natriuretic peptide level. 4. Treatment with SCH 42495 caused a significant reduction in the pulmonary vascular remodelling and ventricular hypertrophy in hypoxic rats after 10 days. Plasma atrial natriuretic peptide levels were significantly elevated in both SCH 42495-treated and control hypoxic animals (n = 8) after 10 days when compared with the normoxic groups. However, there was no difference in plasma ANP levels between SCH 42495-treated and control chronic hypoxic groups at day 10. 5. Treatment with SCH 42495 leads to a decrease in cardiovascular remodelling secondary to chronic hypoxia in rats. A local action of atrial natriuretic peptide within the pulmonary vasculature may be responsible for this effect. Modulation of atrial natriuretic peptide may have therapeutic potential in the management of conditions characterized by pulmonary hypertension and pulmonary vascular remodelling.

Effects of continuous infusion of atrial natriuretic peptide on the pulmonary hypertension induced by chronic hypoxia in rats

1991 ◽  
Vol 81 (3) ◽  
pp. 379-385 ◽  
Author(s):  
L. Zhao ◽  
R. J. D. Winter ◽  
T. Krausz ◽  
J. M. B. Hughes
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Atrial Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Pulmonary Artery Pressure ◽  
Chronic Hypoxia ◽  
Systemic Blood Pressure ◽  
Artery Pressure ◽  
Pulmonary Vascular Remodelling ◽  
Atrial Natriuretic

1. The effects of the continuous infusion of atrial natriuretic peptide on the development of pulmonary hypertension were studied in rats exposed to chronic hypoxia. 2. Continuous intravenous infusion of two doses of synthetic rat atrial natriuretic peptide, 300 ng/h per rat (0.10 pmol/h per rat) and 800 ng/h per rat (0.28 pmol/h per rat), attenuated the development of pulmonary hypertension in rats exposed to chronic hypoxia (fractional concentration of oxygen in inspired air = 10%) for 7 days: (i) the pulmonary artery pressure (mean ± sd) in the vehicle-treated hypoxic group was 45 ± 6 mmHg compared with 28 ± 6 mmHg in the vehicle-treated normotoxic group (n = 8, P < 0.001); (ii) treatment with atrial natriuretic peptide in normoxia did not alter the pulmonary artery pressure, systemic blood pressure or heart rate; (iii) treatment with atrial natriuretic peptide in hypoxia resulted in a lower pulmonary artery pressure in the group treated with 800 ng of atrial natriuretic peptide/h per rat (38 ± 8 mmHg, P < 0.05 compared with the vehicle-treated hypoxic group) without affecting the systemic blood pressure or heart rate. 3. Chronic hypoxia resulted in an extension of vascular smooth muscle towards the periphery of the lung with the development of muscle in normally non-muscularized vessels (remodelling). Quantitative assessment of the small pulmonary vessels (external diameter 25–55 μm) showed that atrial natriuretic peptide treatment reduced pulmonary vascular remodelling in hypoxia (the percentage of thick-walled vessels in the peripheral lung hypoxic vehicle-treated group was 25 ± 6 compared with 19 ± 4 in the group given 300 ng of atrial natriuretic peptide/h per rat and 17 ± 7 in the group given 800 ng of atrial natriuretic peptide/h per rat, means ± sd, both P < 0.01 compared with the vehicle-treated normoxic group). 4. These data show that infusion of synthetic atrial natriuretic peptide attenuated the pulmonary vascular remodelling and associated pulmonary hypertension produced by chronic hypoxia.

Clearance of brain natriuretic peptide in patients with chronic heart failure: indirect evidence for a neutral endopeptidase mechanism but against an atrial natriuretic peptide clearance receptor mechanism

1992 ◽  
Vol 82 (6) ◽  
pp. 619-623 ◽  
Author(s):  
Chim C. Lang ◽  
Joseph G. Motwani ◽  
Wendy J. R. Coutie ◽  
Allan D. Struthers
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Atrial Natriuretic Peptide ◽  
Human Brain ◽  
Brain Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Neutral Endopeptidase ◽  
Striking Similarity ◽  
Plasma Atrial Natriuretic Peptide ◽  
Atrial Natriuretic

1. Brain natriuretic peptide is a new natriuretic hormone with striking similarity to atrial natriuretic peptide, but there are no previous data concerning its clearance in man. Two pathways of clearance for atrial natriuretic peptide are recognized: degradation by neutral endopeptidase and binding to atrial natriuretic peptide clearance receptors. We have examined the effect of candoxatril, an inhibitor of neutral endopeptidase (dose range 10–200 mg), and the effect of an infusion of a pharmacological dose [45 μg (90 μg in two patients)] of synthetic human atrial natriuretic peptide on plasma human brain natriuretic peptide-like immunoreactivity levels in seven patients with mild to moderate chronic heart failure. 2. Plasma human brain natriuretic peptide-like immunoreactivity levels were elevated in all patients (mean ± sem 22.0 ± 6.2 pmol/l) compared with healthy control subjects (1.3 ± 0.2 pmol/l, n = 11). 3. In all patients, candoxatril increased both plasma atrial natriuretic peptide (P < 0.05) and plasma human brain natriuretic peptide-like immunoreactivity (P < 0.05) levels. 4. By contrast, an exogenous infusion of atrial natriuretic peptide had no effect on plasma human brain natriuretic peptide-like immunoreactivity levels despite increasing the plasma atrial natriuretic peptide concentration to 424 ± 74 pmol/l, which is a level of atrial natriuretic peptide which would have ‘swamped’ all atrial natriuretic peptide clearance receptors. 5. We have therefore shown that plasma human brain natriuretic peptide-like immunoreactivity levels in chronic heart failure are increased by a neutral endopeptidase inhibitor, but are unchanged by an exogenous infusion of atrial natriuretic peptide. Our results suggest that in patients with chronic heart failure, degradation by neutral endopeptidase is an important pathway for clearance of brain natriuretic peptide. By an indirect approach, we did not find any evidence of a role for atrial natriuretic peptide clearance receptors in the metabolism of brain natriuretic peptide in these patients. Although this is in agreement with work in vitro, there could be alternative explanations for the lack of a change in circulating human brain natriuretic peptide-like immunoreactivity during exogenous administration of atrial natriuretic peptide.

Evaluation of SQ 28 603, an inhibitor of neutral endopeptidase, in conscious monkeys

1991 ◽  
Vol 69 (10) ◽  
pp. 1609-1617 ◽  
Author(s):  
Andrea A. Seymour ◽  
Benoni Abboa-Offei ◽  
Magdi M. Asaad ◽  
W. Lynn Rogers
Keyword(s):  
Blood Pressure ◽  
Atrial Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Sodium Excretion ◽  
Neutral Endopeptidase ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Excretory Function ◽  
Plasma Atrial Natriuretic Peptide ◽  
Atrial Natriuretic

The potent neutral endopeptidase inhibitor SQ 28 603 (N-(2-(mercaptomethyl)-1-oxo-3-phenylpropyl)-β-alanine) significantly increased excretion of sodium from 4.9 ± 2.3 to 14.3 ± 2.1 μequiv./min and cyclic 3′,5′-guanosine monophosphate from 118 ± 13 to 179 ± 18 pmol/min after intravenous administration of 300 μmol/kg (~80 mg/kg) in conscious female cynomolgus monkeys. SQ 28 603 did not change blood pressure or plasma atrial natriuretic peptide concentrations in the normal monkeys. In contrast, 1-h infusions of 3, 10, or 30 pmol∙kg−1∙min−1 of human atrial natriuretic peptide lowered blood pressure by −3 ± 4, −9 ± 4, and −27 ± 3 mmHg (1 mmHg = 133.322 Pa), increased cyclic guanosine monophosphate excretion from 78 ± 11 to 90 ± 6, 216 ± 33, and 531 ± 41 pmol/min, and raised plasma atrial natriuretic peptide from 7.2 ± 0.7 to 21 ± 4, 62 ± 12, and 192 ± 35 fmol/mL without affecting sodium excretion. In monkeys receiving 10 pmol∙kg−1∙min−1 of atrial natriuretic peptide, 300 μmol/kg of SQ 28 603 reduced mean arterial pressure by −13 ± 5 mmHg and increased sodium excretion from 6.6 ± 3.2 to 31.3 ± 6.0 μequiv./min, cyclic guanosine monophosphate excretion from 342 ± 68 to 1144 ± 418 pmol/min, and plasma atrial natriuretic peptide from 124 ± 8 to 262 ± 52 fmol/mL. In conclusion, SQ 28 603 stimulated renal excretory function in conscious monkeys, presumably by preventing the degradation of atrial natriuretic peptide by neutral endopeptidase.Key words: atrial natriuretic peptide, neutral endopeptidase, natriuresis, cyclic guanosine monophosphate.

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